Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with AIDS and non-AIDS Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and the plasmablastic variant of multicentric Castleman disease (MCD) [Chang et al., 1994]. KSHV associated pathogenesis is regulated by KSHV lytic infection and infection-induced aberrant cytokine production [Gallo, 1998]. Viruses are extremely well adapted to their hosts. KSHV entry and infection is dependent on the pre-existing intracellular signaling of target cells, apart from the interactions between envelope associated glycoproteins and target cell receptors. Raf has been identified as an oncogene in human cancers [Davies et al., 2002]. A broad array of solid tumors are known to constitutively express Ras/Raf components of the mitogen-activated protein kinase (MAPK) pathway of signaling;including AIDS-related KS [Paris et al., 1996;Mercer and Pritchard, 2003]. In two elaborate studies Raf associated signaling was demonstrated to significantly enhance KSHV infection and angiogenesis, a hallmark of tumorigenesis [Akula et al., 2004;Akula et al., 2005]. The focus of the project is to examine the manner by which Raf enhances KSHV infection and pathogenesis. The two specific aims to examine this hypothesis are, (1) To determine the effect of Raf associated signaling on the virus infection, and (2) To determine the effect of Raf/MEK/ERK pathways on the autocrine loop of growth factors (GFs) / inflammatory cytokines (ICs). There are three good reasons for why the proposed study is crucial and they are as follows, (1) there is lack of in-depth knowledge on the effects of such elevated levels of oncoprotein Raf on KSHV associated pathogenesis;(2) The proposed studies will help us delineate the exact mechanism by which Raf regulates KSHV infection and pathogenesis;and (3) In recent years there has been modest success with the use of Raf kinase inhibitors to treat a variety of cancer conditions. Hence, it would be logical to understand the exact mechanism by which Raf associated signaling alters both KSHV infection and angiogenesis before we go to the next level of proposing studies to test the effect of specific inhibitors on KSHV pathogenesis using in vivo models. PUBLIC HEALTH RELEVANCE: Realization of the proposed research goals will advance our knowledge on the role of tumor causing protein Raf in KSHV biology. Such a study will facilitate future research aimed at developing anti-viral/cancer drugs to control KSHV associated pathogenesis.